L-carnitine (3-hydroxy-4-N-trimethylamino-butyrate), the biologically active and naturally occurring form of carnitine, is a quaternary amine that is required in energy metabolism in mammals. Carnitine is a water soluble organic compatible solute with various biological functions, mainly as a carrier of acyl moieties, such as long chain fatty acids. Carnitine is required for the transport of fatty acids from the cytosol into the mitochondria for beta-oxidation during the breakdown of lipids for the generation of metabolic energy. Carnitine is also known to have antioxidant activity.
To exert its metabolic function, carnitine forms esters with a wide range of fatty acyl groups (i.e. acylcarnitines), a reaction mediated by an enzyme localized to the outer mitochondrial membrane, known as carnitine acyltransferase (e.g. carnitine palmitoyltransferase). The resulting acylcarnitine esters can be transported over the inner mitochondrial membrane into the mitochondrial matrix, where carnitine is separated from the fatty acid chain. The fatty acid proceeds to oxidation, while the free carnitine can be transported back out of the mitochondria to allow the transfer process to continue.
In humans, carnitine may be obtained from food or by endogenous biosynthesis. L-carnitine is biosynthesized primarily in the liver and kidneys from the amino acids lysine (via trimethyllysine) and methionine. Lysine provides the carbon backbone of carnitine while the 4-N-methyl groups originate from methionine. Krajcovicová-Kudlácková et al. have studied the correlation between lysine and methionine intake, and the plasma level of carnitine (Krajcovicová-Kudlácková et al., Physiol Res. 2000; 49(3):399-402).
Vitamin C (also known as ascorbic acid) is essential to the synthesis of carnitine, as it is required for the enzymatic activity of trimethyl-lysine (TML) dioxygenase, the first enzyme in the carnitine synthesis chain. Oxidized vitamin C can be reduced back to its un-oxidized (reduced) state via, inter alia, elevating cysteine levels.
Carnitine molecules, either exogenously-consumed or endogenously-synthesized, enter cells via special transporters. Carnitine molecules are found mainly in brain, heart, muscles, nerve tissue and sperm.
Because of its central role in transporting fatty acids to the site of oxidation, adequate levels of carnitine are required for normal fatty acid and energy metabolism in tissues.
Sufficient levels of carnitine are particularly important in body parts that require high energy and utilize fatty acids as an energy source, such as muscles.
Carnitine is commercially available as a nutritional supplement. Carnitine is also available as a prescription drug for injection or oral administration, for example CARNITOR® and LEVOCARNITINE™, which are indicated for the treatment of primary systemic carnitine deficiency, and for acute and chronic treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency. Carnitine supplementation is used in some medical conditions, such as mitochondrial diseases, including mitochondrial myopathies, and neuromuscular disorders. It is sometimes used by athletes in order to improve performance.
Thiol (—SH) containing compounds are a type of molecules capable of neutralizing several types of damaging oxidative species, thus acting as reducing reagents. The activity of this group of compounds is mainly due to the sulfur atom they comprise which participates in nucleophilic attack on toxic electrophiles, scavenging free radicals, effecting repair of damaged targets through hydrogen atom donation, altering the redox status of the cell, or affecting gene transcription or protein function.
WO 2002/034202 discloses an antioxidant compound characterized by (a) a peptide including at least three amino acid residues of which at least two are cysteine residues, each having a readily oxidizable sulfhydryl group for effecting antioxidation; and at least two peptide bonds, each being cleavable by at least one intracellular peptidase; and (b) a first hydrophobic or non-charged moiety being attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety being attached to a carboxy terminal of the peptide via a second bond, the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to provide the antioxidant compound with membrane miscibility properties for permitting the antioxidant compound to cross cellular membranes; wherein cleavage of the at least two peptide bonds by the at least one intracellular peptidase results in generation of a plurality of antioxidant species, each including one of the cysteine residues having the readily oxidizable sulfhydryl group and which is also active in effecting antioxidation, thereby providing for a plurality of different antioxidant species acting in synergy in exerting antioxidation.
WO 2012/098546, to the inventor of the present invention and others, published after the priority date of the present application, discloses potent compounds having combined antioxidant, anti-inflammatory, anti-radiation and metal chelating properties. Short peptides having said properties and methods and uses of such short peptides in clinical and cosmetic applications are disclosed. Among other peptides, Cys-Lys-Met-Cys (SEQ ID NO: 1) and Cys-Met-Lys-Cys (SEQ ID NO: 2) are disclosed.
Effective compositions and methods for increasing carnitine level in tissues, particularly muscle tissue, are desired.